Taxanes are a family of compounds that were originally identified in extracts of the bark of the yew tree (Taxus). Paclitaxel (Taxol®) and docetaxel (Taxotere®) are taxanes with broad antitumor activity. These drugs were originally approved for use in breast or ovarian tumor subjects, but they have activity against diverse tumors including lymphoma, non-small-cell lung, head and neck, gastric, bladder, prostate, and other carcinomas. Dosing and scheduling of these drugs have been optimized throughout the last two decades. Adverse effects caused by taxane treatment include severe hypersensitivity reaction, neutropenia, peripheral neuropathy, myalgia/arthralgia, skin and nail disorders, and alopecia. Neutropenia is the major dose-limiting toxicity of treatment with paclitaxel, while the frequency of peripheral neuropathy appears to increase with cumulative dose. Although the incidence of severe hypersensitivity reactions has been reduced by the use of premedication, cumulative peripheral neuropathy and neutropenia persist as challenges to optimal treatment with taxanes.
Taxanes are part of the larger family of anti-cancer drugs whose mechanism of action targets microtubules (MTs). Both paclitaxel and docataxel bind to the f3-tubulin subunit and stabilize MTs. This stabilization of the MTs leads to mitotic arrest and subsequent apoptosis. Other compounds with a similar mechanism of action include the epothilones, discodermolide, eleutherobin, the sarcodictyins, and the laulimalides (He et al., (2001) Drug Discovery Today 6:1153-1164).
One of the primary proteins involved in taxane elimination and distribution is ABCB1 (also known as multi-drug resistance 1 (MDR1) or P-glycoprotein). ABCB1 is a member of the ATP-binding cassette family of efflux transporters that are expressed in several tissues, including tissues with excretory function, neural stem cells, the blood-brain-barrier, and hematopoietic precursor cells. Although ABCB1 has not been detected in peripheral nerve cells, the transfer of drugs across the systemic circulation to the peripheral nerves is regulated by the blood-nerve barrier consisting of capillary endothelial cells. The cells that make up the blood-nerve barrier express ABCB1 and are thought to protect the peripheral nervous tissue by transporting toxic substances from the nervous system back into the systemic circulation.
Due to the severity of adverse effects resulting from administration of taxanes and other MT-stabilizing agents, methods for identifying individuals at increased risk for these side effects prior to commencement of treatment are needed.